Pimasertib (AS-703026)

Catalog No.S1475 Synonyms: MSC1936369B, SAR 245509

Pimasertib (AS-703026) Chemical Structure

Molecular Weight(MW): 431.20

Pimasertib (AS-703026) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 of 5 nM-2 μM in MM cell lines. Phase 2.

Size Price Stock Quantity  
In DMSO USD 160 In stock
USD 90 In stock
USD 150 In stock
USD 270 In stock
USD 450 In stock
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3 Customer Reviews

  • Western blot analysis showing HSP27 up-regulation on treatment of MKN-45 cells with the 2 indicated MEK1/2 kinase inhibitors (AS703026: 0.5 uM; PD98059: 10 uM) for the indicated time. Inset: effectiveness of the inhibitors in reducing Erk1/2 phosphorylation.

    FASEB J 2014 10.1096/fj.13-247924. Pimasertib (AS-703026) purchased from Selleck.

    GH+E2-induced ERK phosphorylation was examined by Western Blot in T47D cells pre-treated with increasing doses of AS703026.

    Endocrinology 2013 154(9), 3219-27. Pimasertib (AS-703026) purchased from Selleck.

  • After starved in serum-free medium for 24h, T47D cells incubated with the indicated concentrations of AS703026 for 3h,followed by 20-minute stimolation of 100ng/ml EGF.

    Dr. Zhang of Tianjin Medical University. Pimasertib (AS-703026) purchased from Selleck.

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Biological Activity

Description Pimasertib (AS-703026) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 of 5 nM-2 μM in MM cell lines. Phase 2.
Features A novel, highly selective and potent allosteric inhibitor of MEK1/2.
Targets
MEK1/2 (MM cell line) [1]
(Cell-free assay)
5 nM-2 μM
In vitro

AS703026 is a novel, selective, orally bioavailable MEK1/2 inhibitor that binds to the distinctive MEK allosteric site and therefore exhibits exquisite kinase selectivity. AS703026 inhibits growth and survival of human multiple myeloma (MM) cells, including U266 and INA-6, with IC50 of 5 nM and 11 nM, respectively. Such an inhibitory effect by AS703026 is mediated by G0-G1 cell cycle arrest and is accompanied by reduced expresson of the MAF oncogene. AS703026 further induces apoptosis via caspase-3 and PARP cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). [1] AS703026 may be an effective therapy in colorectal cancer caused by K-Ras mutation. AS703026 (10 μM) effectively inhibits the ERK pathway, proliferation, and transformation in human DLD-1 colorectal cancer cells what carry a mutant allele of K-Ras (D-MUT). [2]

In vivo AS703026 (15 and 30 mg/kg) significantly inhibits tumor growth in a human plasmacytoma xenograft model of H929 MM cells. This can be correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels. [1] AS703026 (10 mg/kg) inhibits tumor growth, and markedly decreases p-ERK level in a xenograft mouse model of human K-Ras mutated (D-MUT) colorectal tumor. [2]

Protocol

Kinase Assay:[3]
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MEK1 enzyme assays:

AS703026 is dissolved in 2.5% DMSO. Activated diphosphorylated MEK (pp-MEK) assays contained 40 μM 33P-γATP (AppKm 8.5 μM), 0.5 nM human-activated MEK1 or MEK2, 1 μM kinase-dead ERK2 (AppKm 0.73 μM). All assays are done in buffer containing 20 mM HEPES (pH 7.2), 5 mM 2-mercaptoethanol, 0.15 mg/mL BSA, and 10 mM MgCl2. The final concentration of 33P- ATP is 0.02 μCi/μL for all the assays. pp-MEK kinase reactions are stopped after 40 min by transferring 30 μL of reaction mixture to Durapore 0.45-μm filters plates containing 12.5% TCA. Filters are dried and read with liquid scintilant on a TopCount. Concentration response data are analyzed for IC50. 0.2 nM recombinant human MEK1 or MEK2 is preincubated with vehicle or with AS703026 for 40 minutes in reaction buffer to determine IC50 of initially unphosphorylated MEK (u-MEK). Phosphorylation/activation is initiated by the addition of a final concentration of 20 nM final B-RafV600E and 30 μM final ATP for 10 min. B-Raf activity is then quenched by addition of the B-Raf inhibitor SB590885 (final concentration 100 nM), and MEK kinase activity is assayed by the addition of 1 μM KD-ERK2 and 0.02 μCi/μL 33P-ATP in reaction buffer. The kinase reactions are stopped after 90 min by transferring 30μL of reaction mixture to a Durapore filter plate, and read as above.
Cell Research:[1]
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  • Cell lines: U266 and INA-6 cells
  • Concentrations: 2 nM - 20 μM (stock: 10 mM in DMSO)
  • Incubation Time: 48 hours
  • Method: Cytotoxicity assays for AS703026 are assessed by measuring both [3H]thymidine incorporation and MTT dye absorbance. Cells (1 × 104 per well) are cultured in 96-well plates for 3 days. For the [3H]thymidine incorporation assay, cells are pulsed with 18.5 kBq/well [3H]thymidine for 6 hours, harvested onto glass fibre filters, and counted in a β-scintillation counter. Cell cycle analysis is assessed by propidium iodide (PI) staining using flow cytometry. AS703026-induced apoptosis is determined by annexin-V/PI staining and flow cytometric data analysis.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: H929 MM xenografts are established in CB17 (SCID) mice
  • Formulation: 10 mg/mL, dissolved in 0.5% carboxymethylcellulose / 0.25% Tween20
  • Dosages: 15 or 30 mg/kg
  • Administration: Oral gavage twice daily
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 86 mg/mL (199.44 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 0.5% CMC+0.25% Tween 80 30 mg/mL

* 1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 431.20
Formula

C15H15FIN3O3

CAS No. 1236699-92-5
Storage powder
in solvent
Synonyms MSC1936369B, SAR 245509

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01992874 Completed Neoplasms EMD Serono November 2013 Phase 1
NCT01985191 Completed Neoplasm Malignant Sanofi|Merck KGaA November 2013 Phase 1
NCT01936363 Active, not recruiting Ovarian Cancer EMD Serono|Sanofi September 2013 Phase 2
NCT01693068 Completed N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma EMD Serono|Merck KGaA December 2012 Phase 2
NCT01713036 Completed Locally Advanced or Metastatic Solid Tumors Merck KGaA November 2012 Phase 1
NCT01668017 Terminated Advanced Solid Tumors|Hepatocellular Carcinoma Merck KGaA|Merck Serono Co., Ltd., Japan September 2012 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID